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2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans

Award Number: R44AG055184
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans - Approximately 5.2 million Americans are affected by Alzheimer’s disease (AD), and up to 13 million will be affected by 2050. At present, there is no preventive or curative treatment for AD or in age-related cognitive decline and clinical trials of cognitive-modifying compounds have not succeeded in identifying an effective treatment. Despite a lot of efforts, no candidates are available to slow down the development or even cure this devastating disease. Although most of the efforts are focusing on the amyloid and the tau pathways, we have taken a different approach and targeted oxidative stress. Oxidative stress is a major pathogenic mechanism that underlies both the pre-clinical development and subsequent progression of AD, and one that could potentially be targeted preventively as well as therapeutically. Levels of reactive oxygen species (ROS) increase during inflammation, mitochondrial dysfunction, and metal redox cycling catalyzed by A, all processes associated with AD development. ROS-catalyzed lipid peroxidation generates bifunctional electrophiles (BFEs). We have shown that BFEs generated by oxidative stress accelerate Aß oligomerization, generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid-derived diffusible ligands. They inhibit proteosomal activity, cause mitochondrial dysfunction, and promote dendritic cell activation of T cells. Importantly, we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains, and correlate positively with both the CERAD plaque score and the Braak stage. We have found that 2-hydroxybenzylamine (2-HOBA) reacts 1,600-fold faster with BFEs than lysine, preventing protein modification in vitro and in vivo. Importantly, in hApoE4 transgenic mice, 2-HOBA inhibits all the effects of BFEs described above, and prevents working memory deficit. 2-HOBA, a natural product present in buckwheat seeds, has been developed for use in humans by Metabolic Technologies, Inc. (MTI, Ames, IA). The chemical, manufacturing and control data have been generated and pre-clinical pharmacology and toxicology data are currently being collected. In this project, we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics, metabolism, and safety of 2-HOBA. We also propose to establish brain penetrance of 2-HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	000	3	12/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	004	3	11/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,636
2020	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	003	2	11/15/2019	SUPPLEMENT FOR EXPANSION	-$150,636
2020	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	001	2	11/6/2019	NON-COMPETING CONTINUATION	$0
2020	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	002	2	11/15/2019	NON-COMPETING CONTINUATION	$0
2020	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	005	3	12/20/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	006	3	8/19/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2016	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	000	1	11/5/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	002	3	7/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$605,216
2019	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	000	2	7/6/2019	NON-COMPETING CONTINUATION	-$605,216
2019	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	001	2	7/7/2019	SUPPLEMENT FOR EXPANSION	$0
2019	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	004	3	8/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$605,216
2019	2017	MTI BIOTECH INCORPORATED	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	003	3	7/26/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$605,216
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $834,273 )
2017	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	001	2	9/22/2017	SUPPLEMENT FOR EXPANSION	$150,636
2017	2017	METABOLIC TECHNOLOGIES, INC.	2711 S LOOP DR STE 4400	AMES	IA	50010	STORY	USA	Aging Research	000	2	6/21/2017	NON-COMPETING CONTINUATION	$683,637
														Subtotal = $834,273

Issue Date FY: 2016 ( Subtotal = $672,479 )
2016	2016	METABOLIC TECHNOLOGIES, INC	2625 NORTH LOOP DR, STE 2150	AMES	IA	50010	STORY	USA	Aging Research	000	1	9/22/2016	NEW	$672,479
														Subtotal = $672,479

Grand Total All Awards = $1,506,752

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2-Hydroxybenzylamine for the prevention of Alzheimer's disease: Initial evaluation in humans

Award Number: R44AG055184

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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